Inflammation is a component of the pathogenesis of many human and animal diseases, as well as arising as a result of physical, chemical or traumatic damage to tissues in a human or animal body. In general, the immune response results in the systemic release of endogenous chemical mediators which cause vasodilation, migration of neutrophils, chemotaxis, and increased vascular permeability. The immune response is essentially the same wherever it occurs and whatever the cause. The response can be acute (short lived) or it may be chronic (long lasting).
Endotoxic shock, sometimes also referred to as septic shock, is thought to occur due to intravascular exposure to large amounts of endotoxin resulting in an inflammation like response. Exposure to endotoxin results in the production of a number of cytokines, including TNFα and IL-1. The complement system and the coagulation cascade, including Factor VII are also stimulated. The result of this reaction can be tissue damage, fever, vasodilation, tachycardia and intravascular coagulation.
An inflammatory response is typically beneficial, giving the site of inflammation increased access to nutrients, oxygen, antibodies and therapeutic drugs, as well as increased fibrin formation and dilution of toxins. However, if inflammation is unwanted or prolonged then it can cause damage to the tissue. In such situations, anti-inflammatory drugs are often used. There are two main types of anti-inflammatory drugs, corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs).
Most of these drugs have unwanted side effects. Prolonged corticosteroid administration is frequently associated with serious side effects that mimic Cushing's disease, a malfunction of the adrenal glands resulting in overproduction of cortisol. Other potential side effects include weight gain, fat deposits in the chest, face, neck and upper back, oedema, hypertension, diabetes, poor wound healing, increased susceptibility to infection, thinning of the skin, mood swings and depression. The most serious side effects of NSAIDS are kidney failure, liver failure, ulcers and prolonged bleeding after an injury or surgery. Some individuals are allergic to NSAIDs and people with asthma are at a higher risk for experiencing a serious allergic reaction to aspirin. There is therefore a need to identify alternative agents which have anti-inflammatory effects.
Chemerin is an abundant protein present in a range of human inflammatory exudates including ascitic and synovial fluid (Wittamer V et al. J Exp Med. Oct. 6, 2003; 198(7):977-985; Meder Wet et al. FEBS Lett. Dec. 18, 2003; 555(3):495-499). Human Chemerin is secreted as a 163 amino acid (aa) precursor referred to as ProChemerin (the Mus musculus, murine equivalent is 162aa) which undergoes N- and C-terminal truncation to generate a 137aa chemotactic protein (140aa in Mus musculus) (Wittamer V et al. J Exp Med. Oct. 6, 2003; 198(7):977-985; Zabel B A et al. J Biol Chem. Oct. 14, 2005; 280(41):34661-34666; Wittamer V et al. J Immunol. Jul. 1, 2005; 175(1):487-493; Samson M et al. Eur J Immunol. May 1998; 28(5):1689-1700). The predicted structure for Chemerin indicates structural similarities to chemokines and it has been described as a “reverse” chemokine, potentially possessing a disordered carboxyl-terminus, an α-pleated sheet and a β-helical amino-terminal domain (Zabel B A et al. Exp Hematol. August 2006; 34(8):1021-1032). The structure is reminiscent of the cystatin fold present in cathelicidins and kininogens which also undergo proteolytic processing to achieve activation (Zabel B A et al. Exp Hematol. August 2006; 34(8):1106-1114; Colman R W, Biol Chem. January 2001; 382(1):65-70; Yamasaki K et al. FASEB J. Oct. 1, 2006 2006; 20(12):2068-2080).